)URQWLHUV Bearing Two Vicinal Spiro Quaternary …mmol) and 2 (0.12 mmol, 1.2 eq) in EtOAc (2.0 mL)...

Organocatalytic Asymmetric Synthesis of Highly

Functionalized Spiro-Thiazolone-Cyclopropane-Oxindoles

Bearing Two Vicinal Spiro Quaternary Centers

Shengzheng Wanga,†,*, Zhongjie Guoa,†, Ying Wub,†, Wei Liuc, Xueying Liua,

Shengyong Zhanga, and Chunquan Shengb,*

a Department of Medicinal Chemistry, School of Pharmacy, Fourth Military Medical

University, 169 Changle West Road, Xi'an, 710032, P.R. Chinab Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical

University, 325 Guohe Road, Shanghai, 200433, P.R. China c School of Food and Biological Engineering, Shaanxi University of Science &

Technology, Weiyang College Park, Xi'an 710021, People’s Republic of China

Electronic Supplementary Material (ESI) for Organic Chemistry Frontiers.This journal is © the Partner Organisations 2019

S1

Table of contents

1. General Information S2

2. General procedure for the organocatalytic Michael-Alkylation

cascade reaction

S2

3. Characterization of products 3 S3

4. Synthetic elaboration of Michael-Alkylation adduct 3a S13

5. X-ray structure of compound 3m S16

6. NMR Spectra and HPLC Profile S17

S2

General Information

All reagents and solvents were reagent grade or were purified by standard

methods before use. 1H NMR and 13C NMR spectra were recorded on Bruker

AVANCE300 or AVANCE400 or AVANCE600 spectrometer (Bruker Company,

Germany), using TMS as an internal standard and CDCl3, CD3OD or DMSO-d6 as

solvent. Multiplicities were given as: s (singlet), d (doublet), t (triplet), dd (double of

doublet) or m (multiplets). Chemical shifts (δ values) and coupling constants (J values)

are given in ppm and Hz, respectively. High resolution mass spectrometry (HRMS)

was recorded on an Agilent 6538 UHD Accurate-Mass Q-TOF LC/MS spectrometer.

TLC analysis was carried out on silica gel plates GF254 (Qindao Haiyang Chemical,

China). Silica gel column chromatography was performed with Silica gel 60G

(Qindao Haiyang Chemical, China). Enantioselectivities were determined by High

performance liquid chromatography (HPLC) analysis employing a Daicel Chiralpak

AD, OD or OZ. Optical rotations were measured on a Perkin-Elmer 343 polarimeter

(c given in g/100 mL) with instruments operating at λ = 589 nm, corresponding to the

sodium D line at 25°C. Absolute configuration of the products was determined by X-

ray.

General procedure for the organocatalytic Michael-Alkylation cascade reaction

N

SO N

H

O

ClN

S

O

NH

O+

catalyst (10 mol%)

Et3N (1.8 eq)EtOAc, -30C

IV

HN

HN

S

F3C

CF3

Ncatalyst:

1 2 3

R1

R3

R1

R3

R2

R2

A solution of catalyst (10 mol %) and Et3N (0.18 mmol, 1.8 eq), substrate 1 (0.10

mmol) and 2 (0.12 mmol, 1.2 eq) in EtOAc (2.0 mL) was stirred at -30°C for 12 h.

After reaction, the solvent was evaporated and the crude product was purified using

flash column chromatography (silica gel, DCM) to afford the desired product 3. For

the preparation of racemic 3, racemic catalyst IV (er = 44 : 56 ) was used.

S3

Characterization of products 3

N

S Ph

O

NH

O

3a

(2'S,3R,3'R)-2'',3'-diphenyl-4''H-dispiro[indoline-3,1'-cyclopropane-2',5''-

thiazole]-2,4''-dione (3a). Faint yellow solid (30 mg), yield 76%. 1H NMR (400 MHz,

CDCl3) δ 4.34 (s, 1H), 6.93 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.27-7.32 (m,

3H), 7.35 (br, 3H), 7.52 (t, J = 7.6 Hz, 2H), 7.68 (t, J = 7.3 Hz, 1H), 8.10 (d, J = 7.7

Hz, 1H), 8.17 (d, J = 8.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 43.28, 45.91, 56.76,

109.78, 122.76, 124.62, 125.67, 128.20, 128.33, 128.58, 128.76, 129.06, 129.46,

131.23, 132.26, 135.12, 140.62, 171.73, 187.41, 195.42. HRMS (ESI+) m/z

calculated for C24H16KN2O2S (M+K): 435.0570, found 435.0568. HPLC (Chiralpak

OD, 0.46 cm I.D. ×25 cm L ×5 um, 25oC, i-propanol/hexane = 20: 80, flow rate 0.8

mL/min, λ = 254 nm): tmajor = 10.88 min, tminor = 20.63 min, ee = 93%; [α]25 D = -68.1

(c = 0.15 in DCM).

N

S Ph

O

NH

O

Br

3b

(2'S,3R,3'R)-4-bromo-2'',3'-diphenyl-4''H-dispiro[indoline-3,1'-cyclopropane-

2',5''-thiazole]-2,4''-dione (3b). Faint yellow solid (39 mg), yield 82%. 1H NMR (400

MHz, CDCl3) δ 5.67 (s, 1H), 6.66 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 8.0 Hz, 1H), 7.31-

7.39 (m, 6H), 7.46 (t, J = 7.8 Hz, 2H), 7.63 (t, J = 7.4 Hz, 1H), 8.06 (t, J = 7.4 Hz, 2H),

8.67 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 38.70, 48.88, 60.19, 109.35, 120.46,

121.90, 128.14, 128.23, 128.45, 128.67, 129.03, 129.65, 129.99, 130.87, 132.12,

135.07, 143.17, 172.57, 186.57, 193.73. HRMS (ESI+) m/z calculated for

C24H15BrKN2O2S (M+K): 512.9675, found 512.9669. HPLC (Chiralpak OD, 0.46 cm

S4

I.D. ×25 cm L ×5 um, 25oC, i-propanol/hexane = 20: 80, flow rate 0.8 mL/min, λ =

254 nm): tmajor = 12.55 min, tminor = 16.38 min, ee = 80%; [α]25 D = 129.8 (c = 0.19 in

DCM).

N

S Ph

O

NH

O

3cBr

(2'S,3R,3'R)-6-bromo-2'',3'-diphenyl-4''H-dispiro[indoline-3,1'-cyclopropane-

2',5''-thiazole]-2,4''-dione (3c). Faint yellow solid (37 mg), yield 78%. 1H NMR (600

MHz, CDCl3) δ 4.30 (s, 1H), 7.06 (s, 1H), 7.25-7.27 (m, 2H), 7.28 (d, J = 8.2 Hz, 1H),

7.34-7.36 (br, 3H), 7.50-7.54 (m, 2H), 7.67 (t, J = 7.4 Hz, 1H), 7.96 (d, J = 8.2 Hz,

1H), 8.15 (m, 2H). 13C NMR (150 MHz, CDCl3) δ 43.44, 45.78, 56.96, 113.51,

122.67, 123.68, 125.82, 127.06, 128.49, 128.58, 128.76, 129.28, 129.50, 131.06,

132.28, 135.44, 142.05, 172.10, 187.47, 195.69. HRMS (ESI+) m/z calculated for

C24H16BrN2O2S (M+H): 475.0116, found 475.0105. HPLC (Chiralpak OZ, 0.46 cm


254 nm): tmajor = 9.83 min, tminor = 19.03 min, ee = 86%; [α]25 D = -55.6 (c = 0.23 in

DCM).

N

S Ph

O

NH

O

3d

Cl

(2'S,3R,3'R)-4-chloro-2'',3'-diphenyl-4''H-dispiro[indoline-3,1'-cyclopropane-

2',5''-thiazole]-2,4''-dione (3d). Faint yellow solid (37 mg), yield 86%. 1H NMR

(600 MHz, CDCl3) δ 5.52 (s, 1H), 6.54 (d, J = 7.2 Hz, 1H), 7.11-7.15 (m, 2H), 7.22 (t,

J = 7.9 Hz, 1H), 7.32-7.39 (m, 5H), 7.45 (t, J = 7.6 Hz, 2H), 7.62 (t, J = 7.1 Hz, 1H),

8.05 (d, J = 8.2 Hz, 2H), 8.79 (s, 1H). 13C NMR (150 MHz, CDCl3) δ 38.87, 48.07,

59.98, 108.85, 119.13, 125.33, 128.22, 128.43, 129.02, 129.70, 129.88, 130.95,

S5

132.08, 133.67, 135.05, 143.08, 172.60, 186.40, 193.65. HRMS (ESI+) m/z

calculated for C24H16ClN2O2S (M+H): 431.0621, found 431.0608. HPLC (Chiralpak


mL/min, λ = 254 nm): tmajor = 11.72 min, tminor = 17.15 min, ee = 73%; [α]25 D = 104.9

(c = 0.29 in DCM).

N

S Ph

O

NH

O

3eCl


2',5''-thiazole]-2,4''-dione (3e). Faint yellow solid (30 mg), yield 70%. 1H NMR (400

MHz, CDCl3) δ 4.31 (s, 1H), 6.91 (s, 1H), 7.14 (d, J = 8.3 Hz, 1H), 7.27 (br, 1H),

7.36-7.38 (m, 3H), 7.51 (t, J = 7.8 Hz, 2H), 7.68 (t, J = 7.4 Hz, 1H), 8.02 (d, J = 8.3

Hz, 1H), 8.14 (d, J = 7.8 Hz, 2H), 8.73 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 43.31,

45.61, 56.84, 110.62, 122.74, 122.99, 126.61, 128.35, 128.44, 128.60, 129.13, 129.38,

130.95, 132.12, 134.68, 135.29, 141.78, 172.15, 187.35, 195.55. HRMS (ESI+) m/z

calculated for C24H16ClN2O2S (M+H): 431.0621, found 431.0623. HPLC (Chiralpak



(c = 0.25 in DCM).

N

S Ph

O

NH

O

3f

Cl


2',5''-thiazole]-2,4''-dione (3f). Faint yellow solid (33 mg), yield 76%. 1H NMR (400

MHz, CDCl3) δ 4.31 (s, 1H), 6.61 (d, J = 8.2 Hz, 1H), 7.23-7.28 (m, 2H), 7.36 (br,

3H), 7.48 (t, J = 7.4 Hz, 2H), 7.65 (t, J = 7.4 Hz, 1H), 8.08-8.11 (m, 3H), 9.03 (s, 1H).

S6

13C NMR (100 MHz, CDCl3) δ 43.44, 45.68, 56.88, 111.05, 125.84, 126.20, 128.26,

128.36, 128.39, 128.57, 128.71, 129.10, 129.46, 130.97, 132.08, 135.30, 139.40,

171.89, 187.21, 195.47. HRMS (ESI+) m/z calculated for C24H16ClN2O2S (M+H):

431.0621, found 431.0617. HPLC (Chiralpak OD, 0.46 cm I.D. ×25 cm L ×5 um,

25oC, i-propanol/hexane = 20: 80, flow rate 0.8 mL/min, λ = 254 nm): tmajor = 12.02

min, tminor = 18.32 min, ee = 90%; [α]25 D = 35.6 (c = 0.19 in DCM).

N

S Ph

O

NH

O

3g

F

(2'S,3R,3'R)-5-fluoro-2'',3'-diphenyl-4''H-dispiro[indoline-3,1'-cyclopropane-

2',5''-thiazole]-2,4''-dione (3g). Faint yellow solid (30 mg), yield 72%. 1H NMR (400

MHz, CDCl3) δ 4.29 (s, 1H), 6.85 (br, 1H), 7.04 (t, J = 8.4 Hz, 1H), 7.35 (br, 2H),

7.53 (t, J = 7.4 Hz, 2H), 7.69 (t, J = 7.3 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H), 8.17 (d, J =

7.5 Hz, 1H), 8.25 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 43.65, 45.84, 56.81, 110.15,

110.23, 113.70, 113.97, 115.13, 115.36, 126.13, 126.23, 128.23, 128.33, 128.39,

128.44, 128.64, 129.12, 129.40, 130.18, 130.92, 132.16, 135.10, 135.29, 136.57,

157.77, 160.16, 171.68, 187.35, 195.66. HRMS (ESI+) m/z calculated for

C24H16FN2O2S (M+H): 415.0917, found 415.0915. HPLC (Chiralpak OD, 0.46 cm


254 nm): tmajor = 11.48 min, tminor = 17.95 min, ee = 83%; [α]25 D = -80.1 (c = 0.21 in

DCM).

N

S Ph

O

NH

O

3h

F

(2'S,3R,3'R)-4-fluoro-2'',3'-diphenyl-4''H-dispiro[indoline-3,1'-cyclopropane-

2',5''-thiazole]-2,4''-dione (3h). Faint yellow solid (33 mg), yield 80%. 1H NMR

S7

(600 MHz, CDCl3) δ 4.87 (s, 1H), 6.51 (d, J = 7.7 Hz, 1H), 6.85 (t, J = 9.3 Hz, 1H),

7.19-7.23 (m, 1H), 7.29-7.30 (m, 2H), 7.36 (br, 3H), 7.46 (t, J = 7.8 Hz, 2H), 7.63 (t, J

= 7.4 HZ, 1H), 8.07 (d, J = 7.5 Hz, 2H), 8.79 (s, 1H). 13C NMR (150 MHz, CDCl3) δ

39.29, 46.20, 58.46, 106.48, 109.88, 111.19, 111.34, 128.40, 128.62, 129.17, 129.88,

130.87, 130.95, 132.28, 135.20, 143.12, 143.16, 158.92, 172.38, 186.45, 194.07.

HRMS (ESI+) m/z calculated for C24H16FN2O2S (M+H): 415.0917, found 415.0913.

HPLC (Chiralpak OD, 0.46 cm I.D. ×25 cm L ×5 um, 25oC, i-propanol/hexane = 20:

80, flow rate 0.8 mL/min, λ = 254 nm): tmajor = 11.96 min, tminor = 21.03 min, ee =

86%; [α]25 D = 14.8 (c = 0.24 in DCM).

N

S Ph

O

NH

O

3iH3C

(2'S,3R,3'R)-6-methyl-2'',3'-diphenyl-4''H-dispiro[indoline-3,1'-cyclopropane-

2',5''-thiazole]-2,4''-dione (3i). Faint yellow solid (25 mg), yield 60%. 1H NMR (300

MHz, CDCl3) δ 2.40 (s, 3H), 4.27 (s, 1H), 6.71 (s, 1H), 6.94 (d, J = 7.9 Hz, 1H), 7.27

(br, 1H), 7.33-7.35 (br, 3H), 7.48 (t, J = 7.8 Hz, 2H), 7.65 (t, J = 7.5 Hz, 1H), 7.94 (d,

J = 8.0 Hz, 1H), 8.13 (d, J = 7.4 Hz, 2H), 8.52 (s, 1H). 13C NMR (75 MHz, CDCl3) δ

21.81, 43.30, 46.16, 56.72, 110.96, 121.78, 123.48, 125.46, 128.22, 128.44, 128.66,

129.17, 129.60, 131.55, 132.43, 135.17, 139.27, 141.00, 172.56, 187.65, 195.45.

HRMS (ESI+) m/z calculated for C25H19N2O2S (M+H): 411.1167, found 411.1163.

HPLC (Chiralpak OZ, 0.46 cm I.D. ×25 cm L ×5 um, 25oC, i-propanol/hexane = 10:

90, flow rate 0.8 mL/min, λ = 254 nm): tmajor = 10.74 min, tminor = 30.25 min, ee =

89%; [α]25 D = -64.7 (c = 0.23 in DCM).

N

S

O

NH

O

3j

CH3

S8

(2'S,3R,3'R)-2''-phenyl-3'-(o-tolyl)-4''H-dispiro[indoline-3,1'-cyclopropane-2',5''-

thiazole]-2,4''-dione (3j). Faint yellow solid (25 mg), yield 62%. 1H NMR (400 MHz,

CDCl3) δ 2.08 (s, 3H), 4.18 (s, 1H), 6.96 (d, J = 7.7 Hz, 1H), 7.16-7.22 (m, 3H), 7.34

(t, J = 7.6 Hz, 2H), 7.53 (t, J = 7.6 Hz, 2H), 7.69 (t, J = 7.5 Hz, 2H), 7.80 (s, 1H), 8.11

(d, J = 7.6 Hz, 1H), 8.17 (d, J = 7.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 19.61,

42.86, 46.19, 56.91, 109.97, 122.83, 124.49, 125.48, 125.54, 128.36, 128.56, 128.75,

129.06, 129.40, 129.79, 130.35, 132.23, 135.13, 137.73, 140.71, 172.31, 187.33,

195.54. HRMS (ESI+) m/z calculated for C25H19N2O2S (M+H): 411.1167, found

411.1160. HPLC (Chiralpak OD, 0.46 cm I.D. ×25 cm L ×5 um, 25oC, i-

propanol/hexane = 20: 80, flow rate 0.8 mL/min, λ = 254 nm): tmajor = 9.43 min, tminor

= 35.79 min, ee = 93%; [α]25 D = -74.3 (c = 0.23 in DCM).

N

S

O

NH

O

3k

CH3

(2'S,3R,3'R)-2''-phenyl-3'-(p-tolyl)-4''H-dispiro[indoline-3,1'-cyclopropane-2',5''-

thiazole]-2,4''-dione (3k). Faint yellow solid (25 mg), yield 62%. 1H NMR (300 MHz,

CDCl3) δ 2.35 (s, 3H), 4.29 (s, 1H), 6.78 (d, J = 7.6 Hz, 1H), 7.11-7.15 (m, 5H), 7.25

(br, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.64 (t, J = 7.4 Hz, 1H), 8.06-8.12 (m, 3H), 8.77 (s,

1H). 13C NMR (75 MHz, CDCl3) δ 21.39, 43.32, 46.15, 56.98, 110.13, 122.77, 124.83,

125.67, 128.32, 128.65, 128.75, 129.15, 129.19, 129.46, 132.36, 135.19, 138.07,

140.94, 172.32, 187.60, 195.48. HRMS (ESI+) m/z calculated for C25H19N2O2S

(M+H): 411.1167, found 411.1160. HPLC (Chiralpak OD, 0.46 cm I.D. ×25 cm L ×5

um, 25oC, i-propanol/hexane = 20: 80, flow rate 0.8 mL/min, λ = 254 nm): tmajor =

9.14 min, tminor = 20.64 min, ee = 91%; [α]25 D = -64.3 (c = 0.14 in DCM).

S9

N

S

O

NH

O

3l

F

(2'S,3R,3'R)-3'-(2-fluorophenyl)-2''-phenyl-4''H-dispiro[indoline-3,1'-

cyclopropane-2',5''-thiazole]-2,4''-dione (3l). Faint yellow solid (26 mg), yield 64%.

1H NMR (400 MHz, CDCl3) δ 4.13 (s, 1H), 6.95 (d, J = 7.7 Hz, 1H), 7.05 (t, J = 8.7

Hz, 1H), 7.18 (t, J = 7.6 Hz, 2H), 7.32-7.38 (m, 3H), 7.53 (t, J = 7.6 Hz, 2H), 7.69 (t, J

= 7.4 Hz, 1H), 7.87 (s, 1H), 8.11 (d, J = 7.8 Hz, 1H), 8.17 (d, J = 7.2 Hz, 2H). 13C

NMR (75 MHz, CDCl3) δ 37.87, 45.52, 55.92, 109.95, 110.02, 115.53, 115.68,

118.76, 118.85, 122.56, 122.90, 124.10, 124.42, 125.80, 128.58, 128.72, 128.95,

129.19, 130.22, 130.27, 131.38, 132.38, 135.01, 135.26, 140.97, 160.63, 162.28,

172.21, 187.41, 195.60. HRMS (ESI+) m/z calculated for C24H16FN2O2S (M+H):

415.0917, found 415.0915. HPLC (Chiralpak OD, 0.46 cm I.D. ×25 cm L ×5 um,

25oC, i-propanol/hexane = 20: 80, flow rate 0.8 mL/min, λ = 254 nm): tmajor = 12.27

min, tminor = 23.76 min, ee = 82%; [α]25 D = -49.7 (c = 0.18 in DCM).

N

S

O

NH

O

3m

Cl

(2'S,3R,3'S)-3'-(2-chlorophenyl)-2''-phenyl-4''H-dispiro[indoline-3,1'-

cyclopropane-2',5''-thiazole]-2,4''-dione (3m). Faint yellow solid (30 mg), yield

70%. 1H NMR (400 MHz, CDCl3) δ 4.17 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 7.18 (t, J =

7.7 Hz, 1H), 7.31-7.35 (m, 3H), 7.39 (d, J = 7.7 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H),

7.53 (t, J = 7.6 Hz, 2H), 7.69 (t, J = 7.5 Hz, 1H), 7.84 (br, 1H), 8.11 (d, J = 7.6 Hz,

2H), 8.17 (d, J = 7.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 41.79, 46.28, 56.41,

109.82, 122.80, 124.39, 125.64, 126.46, 128.44, 128.59, 128.77, 129.02, 129.07,

129.48, 129.57, 131.03, 132.22, 135.15, 135.34, 140.88, 172.14, 187.18, 195.48.

S10

HRMS (ESI+) m/z calculated for C24H16ClN2O2S (M+H): 431.0621, found 431.0614.

HPLC (Chiralpak OZ, 0.46 cm I.D. ×25 cm L ×5 um, 25oC, i-propanol/hexane = 20:

80, flow rate 0.8 mL/min, λ = 254 nm): tmajor = 9.31 min, tminor = 18.37 min, ee = 79%;

[α]25 D = -70.4 (c = 0.25 in DCM).

N

S

O

NH

O

3n

Br

(2'S,3R,3'S)-3'-(2-bromophenyl)-2''-phenyl-4''H-dispiro[indoline-3,1'-

cyclopropane-2',5''-thiazole]-2,4''-dione (3n). Faint yellow solid (32 mg), yield 68%.

1H NMR (400 MHz, CDCl3) δ 4.16 (s, 1H), 6.90 (d, J = 7.7 Hz, 1H), 7.18 (t, J = 7.7

Hz, 1H), 7.24 (t, J = 7.2 Hz, 1H), 7.30-7.35 (m, 2H), 7.44 (d, J = 7.5 Hz, 1H), 7.51 (t,

J = 7.7 Hz, 2H), 7.58 (d, J = 7.9 Hz, 1H), 7.67 (t, J = 7.4 Hz, 1H), 8.11 (d, J = 7.7 Hz,

1H), 8.14 (d, J = 7.6 Hz, 2H), 8.36 (s, 1H). 13C NMR (100 MHz, CDCl3) δ 43.91,

46.53, 56.78, 77.23, 109.83, 122.79, 124.45, 125.50, 125.69, 126.96, 128.58, 128.76,

129.07, 129.74, 131.21, 131.35, 132.23, 132.83, 135.14, 140.92, 172.13, 187.12,

195.47. HRMS (ESI+) m/z calculated for C24H16BrN2O2S (M+H): 475.0116, found

475.0107. HPLC (Chiralpak OD, 0.46 cm I.D. ×25 cm L ×5 um, 25oC, i-


= 38.62 min, ee = 74%; [α]25 D = -49.8 (c = 0.15 in DCM).

N

S

O

NH

O

3o

Br

(2'S,3R,3'R)-3'-(4-bromophenyl)-2''-phenyl-4''H-dispiro[indoline-3,1'-

cyclopropane-2',5''-thiazole]-2,4''-dione (3o). Faint yellow solid (33 mg), yield 69%.

1H NMR (400 MHz, CDCl3) δ 4.24 (s, 1H), 6.95 (d, J = 7.8 Hz, 1H), 7.16-7.20 (m,

3H), 7.35 (t, J = 7.7 Hz, 1H), 7.47-7.55 (m, 4H), 7.67 (t, J = 7.6 Hz, 1H), 8.05 (s, 1H),

S11

8.09 (d, J = 7.7 Hz, 1H), 8.15 (d, J = 7.9 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ

42.40, 45.72, 56.46, 109.86, 122.40, 122.88, 124.31, 125.70, 128.61, 128.95, 129.11,

130.30, 131.14, 131.56, 132.15, 135.26, 140.56, 171.55, 187.18, 195.36. HRMS

(ESI+) m/z calculated for C24H16BrN2O2S (M+H): 475.0116, found 475.0106. HPLC

(Chiralpak OD, 0.46 cm I.D. ×25 cm L ×5 um, 25oC, i-propanol/hexane = 20: 80,

flow rate 0.8 mL/min, λ = 254 nm): tmajor = 11.27 min, tminor = 21.89 min, ee = 90%;

[α]25 D = -62.3 (c = 0.13 in DCM).

N

S

O

NH

O

OMe

3p

(2'S,3R,3'R)-3'-(4-methoxyphenyl)-2''-(p-tolyl)-4''H-dispiro[indoline-3,1'-

cyclopropane-2',5''-thiazole]-2,4''-dione (3p). Faint yellow solid (38 mg), yield 86%.

1H NMR (600MHz， CD3OD) δ: 2.44 (s, 3H), 3.77 (s, 3H), 4.19 (s, 1H), 6.85-6.88

(m, 2H), 6.99 (d, J = 7.83, 1H), 7.07-7.11 (m, 1H), 7.13-7.16 (m, 2H), 7.29-7.33 (m,

1H), 7.36-7.40 (m, 2H), 7.98 (d, J = 7.36 Hz, 1H), 8.00-8.02 (m, 2H). 13C NMR (150

MHz, CD3OD) δ: 20.47, 42.75, 54.32, 56.55, 109.68, 113.35, 121.69, 123.33, 124.62,

124.91, 128.10, 128.47, 129.55, 129.66, 130.30, 141.93, 146.94, 159.49, 172.18,

187.60, 195.66. HRMS (ESI+) m/z calcd for C26H21N2O3S (M + H): 441.1267; found

441.1272. HPLC (Chiralcel OZ, 0.46 mm I.D. ×250 mm L ×5 um, 25oC, i-


= 49.32 min, ee = 73%; [α]25 D = -42.9 (c = 0.10 in DCM).

N

S

O

NH

O

OMeCl

3q

(2'S,3R,3'R)-2''-(4-chlorophenyl)-3'-(4-methoxyphenyl)-4''H-dispiro[indoline-3,1'-

cyclopropane-2',5''-thiazole]-2,4''-dione (3q). Faint yellow solid (37 mg), yield 80%.

S12

1H NMR (600MHz, DMSO-d6) δ: 3.74 (s, 3H), 4.17 (s, 1H), 6.86 (d, J = 8.46 Hz, 2H),

6.96 (d, J = 7.68 Hz, 1H), 7.06 (t, J = 7.45 Hz, 1H), 7.16 (d, J = 8.23 Hz, 2H), 7.30 (t,

J = 7.68 Hz, 1H), 7.68 (d, J = 8.39 Hz, 2H), 7.87 (d, J = 7.66 Hz, 1H), 8.11 (d, J =

8.29 Hz, 2H), 10.97 (s, 1H). 13C NMR (150 MHz, DMSO-d6) δ: 42.61, 46.18, 55.55,

57.39, 110.29, 113.95, 121.74, 123.84, 124.78, 125.41, 129.12, 130.08, 130.31,

130.74, 131.12, 140.53, 142.77, 159.21, 171.44, 187.16, 193.82. HRMS (ESI+) m/z

calcd for C25H18ClN2O3S (M + H): 461.0721; found 461.0724. HPLC (Chiralpak AD,

4.6 mm I.D. ×250 mm L ×5 um, 25oC, i-propanol/hexane = 20: 80, flow rate 0.8


(c = 0.10 in DCM).

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Synthetic Elaboration of Michael-Alkylation Adduct 3a

N

S Ph

O

NH

O

3a

(Ac)2O

DMAP, DCM

N

S Ph

O

NO

Ac4a

yield: 96%

To a solution of 3a (10 mg, 0.025 mmol) in DCM (2 mL), (Ac)2O (3.8 mg, 0.038

mmol) and DMAP (1 mg) were added and the mixture was stirred at room

temperature for overnight. After reaction, the solvent was evaporated and the crude

product was purified using flash column chromatography (silica gel, DCM) to afford

the desired product 4a.

(2'S,3R,3'R)-1-acetyl-2'',3'-diphenyl-4''H-dispiro[indoline-

N

S Ph

O

NO

Ac4a

3,1'-cyclopropane-2',5''-thiazole]-2,4''-dione (4a). Faint yellow solid (10.6 mg),

yield 96%. 1H NMR (400 MHz, CDCl3) δ 2.63 (s, 3H), 4.41 (s, 1H), 7.33-7.43 (m,

4H), 7.45 (t, J = 7.4 Hz, 1H), 7.55 (t, J = 7.8 Hz, 2H), 7.71 (t, J = 7.4 Hz, 1H), 8.16 (t,

J = 7.8 Hz, 2H), 8.17 (d, J = 7.4 Hz, 1H), 8.35 (d, J = 8.2 Hz, 1H). 13C NMR (100

MHz, CDCl3) δ 26.96, 43.39, 46.29, 58.06, 116.22, 123.25, 124.68, 125.29, 128.43,

128.50, 128.64, 129.17, 129.27, 130.75, 132.06, 135.37, 140.14, 170.45, 171.30,

186.22, 194.76. HRMS (ESI+) m/z calculated for C26H19N2O3S (M+H): 439.1116,

found 439.1113. HPLC (Chiralcel OZ, 0.46 mm I.D. ×250 mm L ×5 um, 25oC, i-


= 4.31 min, ee = 92%; [α]25 D = -147 (c = 0.2 in DCM).

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N

S Ph

O

NH

O

3a

HN

S Ph

O

NH

O

4b

MeOH

NaBH4

A solution of compound 3a (0.10 mmol) in MeOH (2.0 mL) was stirred at 0C for 10

min, followed by the addition of NaBH4 (0.20 mmol, 2.0 eq) in portions. Then the

mixture was stirred at room temperature for 2 h. The reaction was quenched by the

addition of H2O (2.0 mL) and the extracted with EtOAc (3 mL 3). The organic

phases were collected and then dried over MgSO4. The solvent was removed under

reduced pressure and the crude product was purified by flash column chromatography

(silica gel, PE: EA = 4: 1) to afford compound 4b-1 (major) and 4b-2 (minor) (32 mg,

yield 80%, dr = 1.8:1) as a white solid.

HN

S

O

NH

O

(2'S,3R,3'R)-2'',3'-diphenyldispiro[indoline-3,1'-cyclopropane-2',5''-thiazolidine]-

2,4''-dione (4b-1). 1H NMR (600MHz, DMSO-d6) δ: 4.01 (s, 1H), 5.85 (s, 1H), 6.94

(d, J = 7.39 Hz, 1H), 6.97-7.01 (m, 1H), 7.02 (d, J = 7.39 Hz, 2H), 7.15-7.20 (m, 4H),

7.20-7.30 (m, 5H), 7.74 (d, J =7.73 Hz, 1H), 9.38 (s, 1H), 10.52 (s, 1H). 13C NMR

(150 MHz, DMSO-d6) δ: 37.32, 43.11, 51.77, 55.68, 109.48, 121.08, 124.94, 125.97,

126.24, 127.47, 127.94, 128.30, 128.57, 128.95, 129.91, 142.47, 142.81, 170.73,

170.89. HRMS (ESI positive) m/z calcd for C24H29N2O3S (M + H): 399.1162; found

399.1159. HPLC (Chiralcel OZ, 0.46 mm I.D. ×250 mm L ×5 um, 25oC, i-


= 27.27 min, ee = 84%; [α]25 D = -34.5 (c = 0.15 in DCM).

S15

HN

S

O

NH

O

(2'S,3R,3'R)-2'',3'-diphenyldispiro[indoline-3,1'-cyclopropane-2',5''-thiazolidine]-

2,4''-dione (4b-2). 1H NMR (600MHz, DMSO-d6) δ: 4.01 (s, 1H), 5.77 (s, 1H), 6.93

(d, J = 7.84 Hz, 1H), 6.96 (t, J = 7.70 Hz, 1H), 7.09-7.11 (m, 2H), 7.20-7.25 (m, 4H),

7.37-7.40 (m, 1H), 7.44 (t, J = 7.45 Hz, 2H), 7.49-7.52 (m, 1H), 7.67 (d, J = 7.45 Hz,

1H), 9.43 (s, 1H), 10.68 (s, 1H). 13C NMR (150 MHz, DMSO-d6) δ: 37.99, 42.81,

53.76, 56.30, 109.60, 121.11, 125.30, 126.51, 127.14, 127.41, 127.86, 128.25, 129.16,

129.27, 129.91, 132.20, 141.17, 142.75, 170.70, 171.25. HRMS (ESI positive) m/z

calcd for C24H29N2O3S (M + H): 399.1162; found 399.1162. HPLC (Chiralpak OZ,

0.46 cm I.D. ×25 cm L ×5 um, 25oC, i-propanol/hexane = 10: 90, flow rate 0.6


(c = 0.15 in DCM).

S16

X-ray structure of compound 3m

N(S)S

(S)

O

NH

(R)

O

3m

Cl

ORTEP drawing of compound 3m. Ellipsoids are shown at the 50% probability level.

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NMR Spectra and HPLC Profile

Compound 3a

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Compound 3b

S19

Compound 3c

S20

Compound 3d

S21

Compound 3e

S22

Compound 3f

S23

Compound 3g

S24

Compound 3h

S25

Compound 3i

S26

Compound 3j

S27

Compound 3k

S28

Compound 3l

S29

Compound 3m

S30

Compound 3n

S31

Compound 3o

S32

Compound 3p

S33

Compound 3q

S34

Compound 4a

S35

Compound 4b (major)

S36

Compound 4b (minor)

S37

Compound 3a

S38

Compound 3b

S39

Compound 3c

S40

Compound 3d

S41

Compound 3e

S42

Compound 3f

S43

Compound 3g

S44

Compound 3h

S45

Compound 3i

S46

Compound 3j

S47

Compound 3k

S48

Compound 3l

S49

Compound 3m

S50

Compound 3n

S51

Compound 3o

S52

Compound 3p

S53

Compound 3q

S54

Compound 4a

S55

Compound 4b (major)

S56

Compound 4b (minor)

)URQWLHUV Bearing Two Vicinal Spiro Quaternary …mmol) and 2 (0.12 mmol, 1.2 eq) in EtOAc (2.0 mL)...

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Transcript of )URQWLHUV Bearing Two Vicinal Spiro Quaternary …mmol) and 2 (0.12 mmol, 1.2 eq) in EtOAc (2.0 mL)...